Diabetes mellitus (DM) is a quite common
chronic disease, and the prevalence of
erectile dysfunction (ED) is three times higher in this large population. Although diabetes-related ED has been studied extensively, the actin-
myosin contractile apparatus was not examined. The mRNAs encoding smooth muscle
myosin (SMM) heavy chains (MHC) and essential light chains (LC(17)) exist as several different alternatively spliced
isoforms with distinct contractile properties. Recently, we provided novel data that
blebbistatin (
BLEB), a specific
myosin II inhibitor, potently relaxed corpus cavernosum smooth muscle (CCSM). In this study, we examine whether diabetes alters SMM expression, alternative splicing, and/or functional activities, including sensitivity to
BLEB. By using
streptozotocin (STZ)-induced 2-mo diabetic rats, functional activities were tested in vivo by intracavernous pressure (ICP) recording during cavernous nerve stimulation and in vitro via organ bath contractility studies. SMM
isoform composition was analyzed by competitive RT-PCR and total SMM,
myocardin, and embryonic SMM (SMemb) expression by real-time RT-PCR. Results revealed that the
blood glucose level of STZ rats was 407.0 vs. 129.5 mg/dl (control). STZ rats exhibited ED confirmed by significantly increased CCSM contractile response to
phenylephrine and decreased ICP response. For STZ rats, SM-B, LC(17a) and SM2
isoforms, total SMM, and
myocardin expression increased, whereas SM-A, LC(17b), and SM1
isoforms were decreased, with SMemb unchanged.
BLEB was significantly more effective in relaxing STZ CCSM both in vitro and in vivo. Thus we demonstrated a novel diabetes-specific effect on alternative splicing of the SMM heavy chain and essential light chain genes to a SMM
isoform composition favoring a heightened contractility and ED. A switch to a more contractile phenotype was supported further by total SMM expression increase. Moreover, the change in CCSM phenotype was associated with an increased sensitivity to
BLEB, which may serve as a novel
pharmacotherapy for ED.